..We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing...

Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project

..Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity...

..Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity...

Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans

..The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease...

..Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS...

..We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity...

OrthoList: a compendium of C. elegans genes with human orthologs

Daniel D ShayeHoward Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York, United States of AmericaPLoS ONE 6:e20085. 2011

..We sought to assess the orthology between C. elegans and human genes to understand better the relationship between their genomes and to generate a compelling list of candidates to streamline RNAi-based screens in this model...

..We suggest that this network of tissue interactions and feedback regulation allows the tissues to equilibrate and fine-tune their expression of downstream genes, which, in turn, coordinates their rates of aging within the animal...

Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans

Ryan DoonanInstitute of Healthy Ageing and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United KingdomGenes Dev 22:3236-41. 2008

..However, loss of the extracellular Cu/ZnSOD sod-4 enhances daf-2 longevity and constitutive diapause, suggesting a signaling role for sod-4. Overall, these findings imply that O(2)(-) is not a major determinant of aging in C. elegans...

..This oxidative stress response thus appears to be both widely conserved and ancient, suggesting that the mesendodermal specification role of SKN-1 was predated by its function in these detoxification mechanisms...

CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans

..This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response...

..One of these loci, sid-1, encodes a conserved protein with predicted transmembrane domains. SID-1 is expressed in cells sensitive to RNAi, is localized to the cell periphery, and is required cell-autonomously for systemic RNAi...

..The COOH-terminal region of Apaf-1 comprises multiple WD repeats, which are proposed to mediate protein-protein interactions. Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis...

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

..These observations suggest that the daf-2 gene network controls longevity by regulating the Mn-SOD-associated antioxidant defense system. This system appears to play a role in efficient life maintenance at the dauer stage...

Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans

..Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function...

..Our findings illustrate the ability of germ cells to be directly converted into individual, terminally differentiated neuron types and demonstrate that a specific chromatin factor provides a barrier for cellular reprogramming...

..Furthermore, we find that GLP-1 signaling regulates a third pathway, in addition to the GLD-1 and GLD-2 pathways and also independent of CYE-1/CDK-2, to promote the proliferative fate/inhibit meiotic entry...

A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity

Joshua WollamDepartment of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of AmericaPLoS Biol 10:e1001305. 2012

..elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans...

..We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream targets. The large number of target genes discovered provides insight into how DAF-16 controls diverse biological functions...

..These findings identify the essential role of signalling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway...

..Two distinct classes of meiotic COs are increased in rtel-1 mutants, and COI and homeostasis are compromised. We propose that RTEL-1 implements the second level of CO control by promoting noncrossovers...

..Thus, translational inhibition, a common pathogenic strategy, can trigger activation of an immune surveillance pathway to provide host defense...

The conserved miR-51 microRNA family is redundantly required for embryonic development and pharynx attachment in Caenorhabditis elegans

W Robert ShawDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United KingdomGenetics 185:897-905. 2010

..Genetic analysis reveals that miR-51 family miRNAs might act in part through CDH-3 to regulate pharynx attachment. This study is the first to assign a function to the miR-51/miR-100 miRNA family in any organism...

The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog

..In conclusion, these data reveal the importance of ubiquitination and proteasome-mediated degradation for the activity and turnover of Notch ICs, and demonstrate that mSel-10 plays a key role in this process...

Research Grants68

..elegans will likely provide unique insights into osmoregulation, signaling mechanisms, and cellular stress and damage repair )rocesses in kidney cells as well as other mammalian cell types and tissues. ..

..For UNC-89, we will explore the structure and activity of its kinase domains, identify the substrates or binding partners for its kinase domains, and identify and study binding partners for its SH3, DH and PH domains. ..

..This work will complement fertility studies in other organisms as well as provide insights into the mechanisms of cell-cell interactions and the diversity of reproductive strategies. [unreadable] [unreadable] [unreadable]..

..The strength of this proposal is that it will use a powerful model system and novel reagents for monitoring pH in living organisms to study fat biology from a unique perspective: that of acid-base homeostasis. ..

..Previous C. elegans meetings have led to the exchange of knowledge, ideas, methods, mutants, and clones, and have been vital in fostering the sense of excitement, collegiality and cooperativity that characterize this field. ..

..Characterize two mutants, seg-1 and seg-2, that suppress the shortened lifespan of gas-1. These results will, for the first time, allow a correlation of the effects of ubiquinone on respiration with those on lifespan. ..

..We also will assess levels of blood glucose, insulin, and IGF-1 and map QTLs for these traits. These QTLs will be mapped using the LXS RI strains, a new RI set and the largest set of RIs ever constructed (77 strains). ..

..We are determining structural models for Notch pathway components in order to better understand pathway function, biology and tumorigenesis, which will have an impact on disease diagnosis, prevention, and treatment. ..

..In addition, because C. elegans is the current genetic model system for parasitic nematodes, elucidating the functions of neuropeptides and their signaling pathways may identify new antihelmintic drug targets. ..

..Modulating loci will be identified by detailed phenotypic analysis. This sensitized screen will provide important resources and fundamental insights into developmental signaling pathways in vertebrates. ..

..These studies will contribute to our understanding of ganglion development and provide insights into the mechanisms through which neurons assemble and partition receptive areas, two fundamental issues in developmental neurobiology. ..

..We will also identify and study the functional mammalian homologues. These findings will improve our understanding of the pathogenesis mechanism of muscular dystrophy in humans and may help to devise new therapeutic strategies. ..

..Further elucidation of the molecular mechanisms of Ler action should lead to the development of chemotherapeutic agents directed against EPEC and related E. coli O157 bacteria. [unreadable] [unreadable] [unreadable] [unreadable]..